GENETICS

1944 Howard PJ. Familial character of fibrocystic disease of the pancreas. Am J Dis Child 1944; 68:330-332.
Philip Howard of Detroit reviewed the previous twelve instances of fibrocystic disease of the pancreas where a familial occurrence had been reported including instances where both or only one of twins had been affected. He reported an unusual number of infant deaths in two families in which proven CF existed and suggested the family furnished an instance of heterozygous inheritance (see Andersen and Hodges, 1946 below).
This is the first suggestion that CF was an inherited disorder - later this was established by Andersen and Hodges (1946 belo

1944 Fanconi G, Botsztejn A. Familial pancreatic fibrosis with bronchiectasis. Schweiz Med Wchnschr 1944; 74:85. (German).
Fanconi’s 1936 report is considered by some Europeans to be the first clear description of cystic fibrosis (Fanconi et al, 1936 above). Here the authors described the family trees of 25 children with fibrocystic disease of the pancreas. They considered, incorrectly at it turned out, that recessive transmission was unlikely as there was consanguinity in only 3 of their cases and the proportion of affected siblings appeared too high. So they postulated the cause to be an early intrauterine toxic factor akin to haemolytic disease of the newborn.
Andersen & Hodges, 1946 (below) were the first to correctly identify the Mendelian recessive mode of transmission, although a heterozygous mode had been suggested as likely by Howard in 1944 (above).

1945 Wissler H, Zollinger HU. Familial congenital cystic fibrosis of pancreas with bronchiectasis. Helv Paediatr Acta 1945; 1 (Suppl 1):3-88.
This paper from Zurich describes the clinical and pathological features of CF noting that lung changes may be absent in “nurslings with pancreatic fibrosis who die early”. The cystic pancreatic changes often are only detected by microscopy and may be overlooked. “It seems highly probable that the inflammatory changes in the pancreas, biliary passages and bronchial walls are the result of a single process… probably due to intrauterine damage of maternal origin… no reasons for accepting a primary avitaminosis as the cause and a recessive hereditary disease is improbable”. These Swiss authors mistakenly considered an hereditary cause of CF to be unlikely and suggested the cause was more likely due to intrauterine damage as had Fanconi & Botsztejn, 1944 (above).

1946 Andersen DH, Hodges RC. Celiac syndrome V. Genetics of cystic fibrosis of the pancreas with consideration of the etiology. Am J Dis Child 1946; 72:62-80.
Investigating 47 of their own families and 56 from the literature, the authors concluded that the familial incidence indicated a hereditary disorder with a recessive mode of inheritance, but which required more than one factor for its expression. Although the incidence in siblings approximates to the 25% expected of a Mendelian recessive trait, the authors observed that an hereditary condition requires more than one factor for its expression.

This was a quite different explanation to that given by Fanconi et al (1944) but in line with that of Bodian, 1952 (below). Andersen continued to believe that “the pulmonary infection is the result of the nutritional deficiency” – obviously she considered this to be the additional factor required.
This is the first clear statement, backed by clinical evidence, that CF is inherited in a Mendelian recessive manner. Others, including David Lawson, would also speculate on the relative contribution of the basic defect and the secondary effects of the defect (such as chest infections and malnutrition) to the ultimate outlook for the patient. i.e. if the secondary effects could be prevented would the outlook be much better? Subsequent progress showed that this was indeed the case in view of the steady improvement in outlook that occured before modification of the basic defect was achieved.

1949 Lowe CU, May CD, Reed SC. Fibrosis of pancreas in infants and children: statistical study of clinical and hereditary features. Am J Dis Child 1949; 78:349-374. [PubMed]
These authors from the University of Minnesota reviewed the hereditary aspects of 134 patients with CF seen over 10 years at the Infant's and Children’s Hospital, Boston where previously May had worked. There were 118 sibships and the authors concluded that the condition was determined by a recessive gene as had Andersen and Hodges (Andersen & Hodges, 1946 above). They noted good weight gain before first symptoms and fair gains thereafter in those who survived. In discussing the clinical features they noted 44 children showed osteoporosis and retarded bone age. They questioned the importance of vitamin A deficiency in the pathogenesis as had others.
This is one of the earliest mentions of osteoporosis in people with CF – a complication that was to become a major problem for adults with CF in the years to come.

1952 Bodian ML. Fibrocystic Disease of the Pancreas. A Congenital Disorder of Mucus Production (Mucosis). London, W Heinemann, 1952.
The first substantial work on CF from the UK by Martin Bodian and his colleagues at the Hospital for Sick Children, Great Ormond Street, London (GOS). Dr. Martin Bodian (1910-1963),(figure 4) had been appointed morbid anatomist at GOS in 1946. Dr Archie Norman (figure 5) was the paediatrician in charge of the CF clinic at GOS and a leading figure in CF care in the UK for many years. Dr. Cedric Carter (1917-1984), (figure 6) was a clinical geneticist who started the first genetic counselling clinic at GOS in 1957.
In the preface of the book Martin Bodian notes the contents encompass almost a decade of work since Donald Paterson diagnosed the first child with CF at Great Ormond Street in 1943. The authors reviewed their own and previously published families and concluded there was a recessive mode of inheritance and suggested parents of a child with CF should be given a 1 in 4 risk of further children being affected; this confirmed the findings of Andersen & Hodges (1946 above) and the earlier suggestion of Howard (1944 above).

1962 Pileggi A. Cystic Fibrosis in a negro. Del Med J 1962; March:97-98. [PubMed]
A black infant admitted with bronchopneumonia at 8 months was diagnosed by three positive sweat tests as having cystic fibrosis. He died after 37 days. At autopsy, in addition to bronchopneumonia, the pancreas showed typical changes of cystic fibrosis. The authors note that at the Babies Hospital New York only 2 children of 397 cases were Negroes – an incidence of approximately 0.5% (di Sant’Agnese Am J Med 1956; 21:406).

1963 Batten J, Mir D, Simon G, Carter C. The prevalence of respiratory disease in heterozygotes for the gene for fibrocystic disease of the pancreas. Lancet 1963; i: 1348-1350. [PubMed]
The incidence of chronic bronchitis in parents of people with CF (obligate heterozygotes) and controls was similar to that reported for the general population – which was remarkably high at that time being 17% of men aged 40-60 years and 8% in women. The authors concluded that “the heterozygous state for fibrocystic disease of the pancreas could not be implicated as an important cause of chronic chest disease or of peptic ulceration”. These results agreed with those of Anderson et al. Med J Aust 1962; 1:965.
These results may not apply today as chronic bronchitis was remarkably common in the general population then due to atmospheric pollution and tobacco smoking.

1968 Harries RL, Riley HD Jr. Cystic fibrosis in the American Indian. Pediatr 1968; 41:733-738.
These were the first two children with CF in the American Indian population. Both patients had convincingly high sweat tests and clinical features and were three years eight months and one year 11 months when reported. A sibling of case one who died had the typical pancreatic changes of cystic fibrosis. Caucasian ancestry, if present, was very distant and only on one side of the family and then three generations back. It was suggested that the rarity of CF in Mongolian and American Indians may be related to their common Asian ancestry before the American Indians crossed the Bering Straits into the Western Hemisphere. [PubMed]

1968 Bhakoo ON, Kumar R, Walia BN. Mucoviscidosis of lung. Report of a case. Indian J Pediatr 1968; 35: 183-185. [PubMed]

1968 Mehta S, Wadhwa UN, Mehta SK, Chhutani PN. Fibrocystic disease of the pancreas in India. Indian Pediatr 1968; 5:185-191. [PubMed]

First two reports of cystic fibrosis in India. Reviewed by Kabra SK et al (Cystic fibrosis in India. Pediatr Pulmonol 2007; 42:1087-1094.) [PubMed]

1974 Kulczycki LL, Schauf V. Cystic fibrosis in blacks in Washington DC. Am J Dis Child 1974; 127:64-67. [PubMed]
An intensive search for black people CF between 1962 to 1971 revealed 16 with cystic fibrosis. The clinical course was similar to the condition in whites. The calculated incidence was estimated as at least one in 17,033 black newborns. Later these findings were confirmed by others. More recently African mutations have been described by Michelle Ramsay and colleagues in South Africa (Carles et al, 1996 below).

1995 Gan K-H, Geus WP, Bakker W, Lamers CBHW, Heijerman HGM. Genetic and clinical features of patients with cystic fibrosis diagnosis after the age of 16 years. Thorax 1995; 50:1301-1304. [PubMed]
Predictably, adult patients with late diagnosis have a better prognosis. The differences between the early diagnosis of 4.6 years (ED) and late diagnosis 27.7 years (LD) were FEV1 52% vs 72.5%; Pseudomonas infection in 70% vs 24%; pancreatic insufficiency 81% vs 12%; homozygous for DF508 58% vs none.
In other series of adults with CF many have been diagnosed late and had other features suggesting many had milder mutations – supported by the high frequency of pancreatic sufficiency. However, it has been emphasised that these patients require just as careful follow up and treatment as those with the more usual clinical picture - rather than waiting until they develop more obvious chest symptoms (Lording A, et al. Pulmonary infection in mild variant cystic fibrosis: implications for care. J Cyst Fibros 2006; 5:101-104). [PubMed]

1995 Gan, K H. Veeze, H J. van den Ouweland, A M. Halley, D J. Scheffer, H. van der Hout, A. Overbeek, S E. de Jongste, J C. Bakker, W. Heijerman, H G. A cystic fibrosis mutation associated with mild lung disease. New Eng J Med 1995; 333:95-99. [PubMed]
Among Dutch patients A455E the second most common mutation and associated with preserved pancreatic function and some residual secretion of chloride across membranes. Thirty three patients with compound heterozygosity for the A455E mutation were compared with matched controls homozygous for the delta F508 mutation. In those with the A455E mutation diagnosis was later (mean age at diagnosis, 15.0 vs. 3.1 years; P < 0.001); fewer had pancreatic insufficiency (21.2 percent vs. 93.9 percent, P < 0.001), and none had diabetes mellitus (0 percent vs. 27.3 percent, P = 0.004). FEV1 and FVC were significantly higher (FEV1, 73.9 vs. 54.3 % predicted P = 0.002) and FVC, 88.7 vs. 76.3 % predicted P = 0.04). Fewer had chronic pseudomonas infection (33.3 vs. 60.6 % P = 0.02).
Although several mutations were known to be associated with less severe pancreatic disease, these findings showed a correlation between the A455E mutation and mild pulmonary disease resulting in a better prognosis than patients homozygous for the delta F508 mutation.

Dr Harry Heijerman (figure 34.1) was the Founding Editor of the Journal of Cystic Fibrosis. Under his guidance the journal was increasingly successful; the editorship was taken over by Prof. Gerd Döring in 2006 (see 2002 Journal of Cystic Fibrosis below)
Harry Heijerman is Physician at Haga Teaching Hospital, Deb Haag in the Netherlands and a leading figure in CF care and research in Europe.

1996 Carles S. Desgeorges M. Goldman A. Thiart R. Guittard C. Kitazos CA. de Ravel TJ. Westwood AT. Claustres M. Ramsay M. First report of CFTR mutations in black cystic fibrosis patients of southern African origin. J Med Genet 1996; 33:802-804. [PubMed]
Cystic fibrosis was thought to be rare in the black populations of Africa and only a few patients have been reported but they had not been studied at the molecular level. This report, from Michelle Ramsay’s laboratory, concerns the detection of CFTR mutations in three black South African patients. One was homozygous for the 3120 + 1G-->A mutation, while the other two were compound heterozygotes each with this mutation on one chromosome. The other mutations were G1249E and a previously unreported in frame 54 bp deletions within exon 17a involving nucleotides 3196-3249 (3196del54).
The 3120 + 1G-->A mutation was first described in black American patients and has been shown to be a relatively common mutation in this population (9-14% of CF chromosomes). It was also found in a black CF patient whose father, the 3120 + 1G-->A carrier, is from Cameroon. These data suggest that it is an old mutation which accounts for many of the CFTR mutations in black Africans (Also Pileggi A. 1962; Kulczycki LL et al, 1964 above and other reports find a low incidence in black patients).

1997 Loirat F, Hazout S, Lucotte G. G542X as a probable Phoenician cystic fibrosis mutation. Hum Biol 1997; 69:419-425. [PubMed]
When analyzed by origin, the frequency of the G542X CF mutation (the second most common CF mutation in Europe after DF508) varies between population groups in Europe being lower in north-eastern Europeans than in south-western Europeans. The more elevated values of G542X frequency correspond to ancient sites of occupation by occidental Phoenicians. N1303K as been linked to ancient Mediterranean populations and G551D associated with ancient Celtic tribes (Cashman SM et al, Hum Hered 1995; 45:6-12. [PubMed].

2000 Mickle JE, Cutting GR. Genotype-phenotype relationships in cystic fibrosis. Med Clin North Am 2000; 84:597-607. [PubMed]
The fact that variability is observed among people with the “classic” form of CF is evidence that other factors are important. The so-called “mild mutations” that allow partial function of CFTR are often associated with pancreatic sufficiency, occasionally identified with normal sweat gland function, and sporadically correlated with mild lung disease; also partially functioning mutants rarely prevent maldevelopment of the male reproductive tract; an exception is 3849 + 10 Kb C-->T.

These observations suggest that certain tissues require different levels of CFTR function to avoid the pathologic manifestations typical of CF. However; It is still true that, in the majority of patients, the outlook is more dependent on the standard of treatment the patient receives and whether that treatment is started before there is irreversible lung damage.

Fig. 15: Professor Garry Cutting. From Johns Hopkins website.

From the Department of Pediatrics McKusick-Nathans Institute of Genetic Medicine. Johns Hopkins University School of Medicine, Baltimore. Prof. Garry Cutting (figure 15) is interested in the molecular biology and human genetics of ion channel disorders. Much of his current work is focused upon cystic fibrosis.

2000 Mekus F, Ballman M, Bronsveld I, Bijman J, Veeze H, Tummler B. Categories of DF508 homozygous cystic fibrosis twin and sibling pairs with distinct phenotypic characteristics. Twin Res 2000; 3:277-293. [PubMed]
A large European twin study searching for features for which the twins were discordant. Monozygotic twins with CF had less discordance than dizygotic twins indicating that, in part, CF severity is modulated by an inherited component in addition to the CFTR itself and the very important environmental factors.
Although there was increasing interest in the effect of modifying genes that affected the course of CF in affected individuals, in practical terms the influence of most was relatively small when compared with the influence of the standard of treatment the patient received.

Professor Ballman (figure 1) is on the Board of the European CF Society and based in the Paediatric Department and CF Centre in Hanover, Germany

2000 Kostuch M, Semczuk A, Szarewicz-Adamczyk W, Gasowska-Giszczak U, Wojcierowski J, Kulczycki L. Detection of CFTR gene mutations in patients suffering from chronic bronchitis. Arch Med Res 2000; 31: 97-100. [PubMed]
The purpose of this study from Poland was to search for CF gene mutations in patients suffering from chronic bronchitis. No less than five of 32 (16%) patients admitted to the Lublin School of Medicine, Poland between 1995 and 1996 with chronic bronchitis had CF gene mutations, all within the DeltaF508 region of the CFTR gene. All positive samples were obtained from patients heterozygous for the DeltaF508 mutation. The presence of the DeltaF508 mutation was considered statistically significant when the study group was compared to the study of Poland's general population. The results suggested an increased presence of the DeltaF508 mutation in Polish patients suffering from chronic bronchitis.

Earlier clinical studies using Shwachman finger print plates from the UK did not show people with unrecognised or mild CF were present among patients considered to have chronic bronchitis (Muir D et al. 1962 above). Also in another study, perhaps more relevant to the present report, there was no increase in the frequency of chronic bronchitis among obligate CF heterozygotes (Batten et al, 1963 above). However, the prevalence of chronic bronchitis was very high in the UK general population at that time (presumably due to the high proportion of smokers and atmospheric pollution) and this may have obscured the influence of the CF carrier state. More recently complete mutational screening of 120 patients with chronic pulmonary disease detected mutations in 11/23 diseminated bronchiectasis, 7/25 emphysema, 5/27 chronic bronchitis, 5/26 lung cancer, 5/8 sarcoidosis (Bombieri et al, 1998). [PubMed] In a more recent study 17.74% of 31 patients with chronic obstructive pulmonary disease had a CFTR mutation (Divac et al, 2004). [PubMed] Although others searching for only the six common mutations found no increase in CFTR mutations in 100 patients with chronic bronchitis (Entzian P et al, 1995). [PubMed] However,  5/11 non-CF individuals who had allergic bronchopulmonary aspergillosis (ABPA) had one CFTR mutation (Miller PW et al, 1996. 8659542.
Also CFTR function has been reported as significantly depressed in smokers (Cantin AM et al. Am J Resp Crit Care Med 2006; 173:1139-1144. 16497995).

2001 Iwasa S, Fujiwara M, Nagata M, Watanabe T. Three autopsied cases of cystic fibrosis in Japan. Pathol Internat 2001; 51:467-472. [PubMed]
The incidence of CF is very low in the Japanese. All three patients initially developed meconium ileus, and hepatobiliary and pancreatic changes became more severe as age increased. None had the DeltaF508 mutation. The authors reviewed 22 Japanese autopsied cases of CF in the literature. They suggested that the high incidence of meconium ileus in Japanese CF patients may relate to a clinically severe phenotype and reflect a different genetic background between Caucasians and Japanese. The incidence of CF in Japanese had been estimated previously at 1:350,000 considering 104 reported cases in 1997 (Yamashiro Y et al, 1997; 24:544-547). [PubMed] Also Nishimori I, Onishi S. Hereditary pancreatitis in Japan: a review of pancreatitis-associated gene mutations. Pancreatology 2001; 1:444-447. [PubMed]

2001 Goldman A. Labrum R. Claustres M. Desgeorges M. Guittard C. Wallace A. Ramsay M. The molecular basis of cystic fibrosis in South Africa. Clin Genet 2001; 59:37-41. [PubMed]
The spectrum of CFTR mutations in three South African populations is presented. To date. a total of 192 white patients (384 chromosomes) with confirmed CF have been tested. deltaF508 accounts for 76% of the CF chromosomes in this group, with 3272-26A-->G, 394delTT and G542X occurring at the following frequencies: 4, 3.6 and 1.3%, respectively. A further 11 mutations account for 6% of CF chromosomes. A total of 91% of the CF-causing mutations can now be detected in the South African white population. Haplotype analysis suggests a founder effect in South Africans of European origin for the two common CFTR mutations, 3272-26A-->G and 394delTT. The diagnosis of CF has been confirmed in 14 coloured and 12 black CF patients. In the coloured population, both the deltaF508 and 3120 + 1G-->A mutations occur at appreciable frequencies of 43 and 29%, respectively. In the black population, the most common CF-causing mutation, the 3120 + 1G-->A mutation, occurs at an estimated frequency of 46%. Four other mutations have been detected, resulting in the identification of a total of 62.5% of mutations in this population.

An interesting paper from Michelle Ramsay's department in South Africa documenting the mutations found in the coloured and black populations.

2002 Bobadilla JL, Macek M, Fine JP, Farrell PM. Cystic fibrosis: A worldwide analysis of CFTR mutations – correlation with incidence data and application to screening. Hum Mutat 2002; 19:575-606. [PubMed]
The results confirmed wide mutational heterogeneity throughout the world. They also examined CF incidence, DeltaF508 frequency, and regional mutational heterogeneity in a subset of populations and there is a significant positive correlation between DeltaF508 frequency and the CF incidence levels of regional populations. Regional analyses were also performed to search for trends in the distribution of CFTR mutations across migrant and related populations; this led to clarification of ancestry-genotype patterns that can be used to design CFTR multi-mutation panels for CF screening programs.

This is an immense study bringing together all the information from over 100 published papers to achieve a global understanding of the population molecular genetics associated with CF in an effort to increase understanding of ancestry-genotype relationships, to compare mutational arrays with incidence and to gain insight for decisions regarding screening program enhancement through CFTR mutational analysis.

2003 Li N. He B. Wang GF. Tang XY.A case report of cystic fibrosis and review of 16 cases of cystic fibrosis in Chinese patients. [Chinese] Chinese Journal of Tuberculosis & Respiratory Diseases 2003; 26:559-562. [PubMed]. A report a case of cystic fibrosis (CF) in a 14-year-old Chinese girl presenting with recurrent productive cough since birth with parasinusitis and otitis media was confirmed to have CF in Peking University First Hospital. Chest CT scan showed bronchiectasis, more severe in the right upper lobe. Sweat tests were taken three times, and the values of Na(+) and Cl(-) were (126.6 +/- 5.4) mmol/L and (108.9 +/- 3.3) mmol/L, respectively. The examination of the pancreas showed no remarkable cystic changes on CT scan and there was no pancreatic insufficiency. Sixteen patients with CF in Chinese reported from 1974 to 1999 were reviewed. Sixteen of the 17 patients (7 males and 9 females, aged from 6 months to 25 years) had clinical data available for analysis. Eleven of them had died, nine before the age of 13. They all suffered from frequent episodes of pneumonia, while 14 had malnutrition and 4 had jaundice. The diagnostic procedures included clinical features, sweat test and autopsy. Four of them had DNA screened and four kinds of novel mutations in the cystic fibrosis transmembrane conductance regulator gene were found. So Chinese patients with CF show similar clinical manifestations to patients in the European and North American populations, but the CFTR mutation was different.

2003 Frangolias DD. Ruan J. Wilcox PJ. Davidson AG. Wong LT. Berthiaume Y. Hennessey R. Freitag A. Pedder L. Corey M. Sweezey N. Zielenski J. Tullis E. Sandford AJ. Alpha 1-antitrypsin deficiency alleles in cystic fibrosis lung disease. Am J Resp Cell Mol 2003; 293):390-396. [PubMed]
The conclusions of this detailed study were that alpha1-AT genotype is not a major contributor to the variability of pulmonary disease severity in cystic fibrosis.

2005 Drumm ML, Konstan MW, Schluchter MD, Handler A, Pace R, Zou F, Zariwala M, Fargo D, Xu A, Dunn JM, Darrah RJ, Dorfman R, Sandford AJ, Corey M, Zielenski J, Durie P, Goddard K, Yankaskas JR, Wright FA, Knowles MR. Gene Modifier Study Group. Genetic modifiers of lung disease in cystic fibrosis. N Eng J Med 2005; 353:1443-1453. [PubMed]
Polymorphisms in genes other than the CFTR gene may modify the severity of pulmonary disease in patients with cystic fibrosis. 808 patients who were homozygous for the DeltaF508 mutation had either severe or mild lung disease (i.e. they were in the lowest or highest quartiles for FEV1). The authors genotyped 16 polymorphisms in 10 genes that had been reported by others as modifiers of disease severity in CF and tested for an association in the patients with severe disease (263 patients) or mild disease (545). In a second study, of 498 patients, with various CFTR genotypes and a range of FEV1 values, they tested for an association of the TGFbeta1 codon 10 CC genotype with low FEV1.
In the first study, significant allelic and genotypic associations with phenotype were seen only for TGFbeta1 (the gene encoding transforming growth factor beta1). The second study confirmed the association of the TGFbeta1 codon 10 CC genotype with more severe lung disease.

2006 McKone EF, Goss CH, Aitkin ML. CFTR genotype as a predictor of prognosis in cystic fibrosis. Chest 2006; 130:1441-1447. [PubMed]
Data from CF Foundation registry on 15,651 patients was analysed and showed that the “high risk” CFTR genotype carried a twofold increased risk of death compared to those with “low risk” genotype. Of patients who died, high risk median age of death 24.2 years and low risk 37.6 years. Most reassurance can be provided for patients in the low risk group although there is substantial phenotypic variability.
The outlook for people with CF is mainly determined by the treatment they receive although a small number certainly do have mutations which are associated with milder disease, often associated with pancreatic sufficiency and a much later presentation and diagnosis.

2006 Li N, Pei P, Bu DF, He B, Wang GF. A novel CFTR mutation found in a Chinese patient with cystic fibrosis. Chin Med J 2006; 119:103-109. [PubMed]
A Chinese girl of 16 years old was diagnosed as having CF at the age of 14 years. A heterozygous novel missense mutation of 699 C --> A, which results in the amino acid change of N189K, was identified in exon 5. In addition, a heterozygous 3821 - 3823 delT mutation in exon 19 was found in CFTR.

CF is very rare on Chinese people; only twenty were reported from 1974 to 2004 were also reviewed in this paper. DelF508 mutation was not found in any of the nine cases whose CFTR mutations were analyzed and suggests that the genotype of Chinese CF may be different from those in Europe and N America.

2009 Bartlett JR, Friedman KJ, Ling SC, et al. Gene Modifier Study Group. Genetic modifiers of liver disease in cystic fibrosis. JAMA 2009; 302:1076-1083. [PubMed]
A subset (approximately 3%-5%) of patients with CF develops severe liver disease with portal hypertension. The objective of the study was to assess whether any of 9 polymorphisms in 5 candidate genes (alpha(1)-antitrypsin or alpha(1)-antiprotease [SERPINA1], angiotensin-converting enzyme [ACE], glutathione S-transferase [GSTP1], mannose-binding lectin 2 [MBL2], and transforming growth factor beta1 [TGFB1]) are associated with severe liver disease in patients with CF. The authors concluded that the SERPINA1 Z allele is a risk factor for liver disease in CF. Patients who carry the Z allele are at greater risk (OR, approximately 5) of developing severe liver disease with portal hypertension.

2000 Kostuch M, Semczuk A, Szarewicz-Adamczyk W, Gasowska-Giszczak U, Wojcierowski J, Kulczycki L. Detection of CFTR gene mutations in patients suffering from chronic bronchitis. Arch Med Res 2000; 31: 97-100. [PubMed]
The purpose of this study from Poland was to search for CF gene mutations in patients suffering from chronic bronchitis. No less than five of 32 (16%) patients admitted to the Lublin School of Medicine, Poland between 1995 and 1996 with chronic bronchitis had CF gene mutations, all within the DeltaF508 region of the CFTR gene. All positive samples were obtained from patients heterozygous for the DeltaF508 mutation. The presence of the DeltaF508 mutation was considered statistically significant when the study group was compared to the study of Poland's general population. The results suggested an increased presence of the DeltaF508 mutation in Polish patients suffering from chronic bronchitis.

Earlier clinical studies using sweat tests from the UK did not show people with unrecognised or mild CF were present among patients considered to have chronic bronchitis (Muir D et al. 1962 above). Also in another study, perhaps more relevant to the present report, there was no increase in the frequency of chronic bronchitis among obligate CF heterozygotes (Batten et al, 1963 above). However, the prevalence of chronic bronchitis was very high in the UK general population at that time (presumably due to the high proportion of smokers and atmospheric pollution) and this may have obscured the influence of the CF carrier state. More recently complete mutational screening of 120 patients with chronic pulmonary disease detected mutations in 11/23 desiminated bronchiectasis, 7/25 emphysema, 5/27 chronic bronchitis, 5/26 lung cancer, 5/8 sarcoidosis (Bombieri et al, 1998). [PubMed]  In a more recent study 17.74% of 31 patients with chronic obstructive pulmonary disease had a CFTR mutation (Divac et al, 2004). [PubMed] Although others searching for only the six common mutations found no increase in CFTR mutations in 100 patients with chronic bronchitis (Entzian P et al, 1995). [PubMed] However,  5/11 non-CF individuals who had allergic bronchopulmonary aspergillosis (ABPA) had one CFTR mutation (Miller PW et al, 1996. [PubMed]). Also CFTR function has been reported as significantly depressed in smokers (Cantin AM et al. Am J Resp Crit Care Med 2006; 173:1139-1144). [PubMed]

2006 Ziedalski TM, Kao PN, Henig NR, Jacobs SS, Ruoss SJ. Prospective analysis of cystic fibrosis transmembrane regulator mutations in adults with bronchiectasis or pulmonary nontuberculous mycobacterial infection. Chest 2006; 130:995-1002. [PubMed]
Fifty adult patients at Stanford University Medical Center with a diagnosis of bronchiectasis and/or pulmonary NTM infection were prospectively characterized by sweat chloride measurement, comprehensive mutational analysis of CFTR, and sputum culture results. A new diagnosis of cystic fibrosis (CF) was established in 10 patients (20%). Sweat chloride concentration was elevated > 60 mEq/dL (diagnostic of CF) in seven patients (14%), and from 40 to 60 mEq/dL in eight patients (16%). The frequency of CFTR mutations was elevated above that expected in the general population: heterozygous DeltaF508 (12% vs 3%), R75Q (14% vs 1%), and intron 8 5T (17% vs 5 to 10%).

2008 Douros K. Loukou I. Doudounakis S. Tzetis M. Priftis KN. Kanavakis E. Asthma and pulmonary function abnormalities in heterozygotes for cystic fibrosis transmembrane regulator gene mutations. Int j clin exp med 2008; 1:345-349. [PubMed] The aim of our study is to evaluate the association between CFTR gene mutations with asthma and pulmonary function abnormalities. For this purpose, 214 mutation carriers were compared to 185 non-carriers. Although the relative risk of asthma did not differ between groups (OR=0.61, 95% CI: 0.23-1.61, p=0.32), the values of FEV1, and FEV1/FVC ratio were lower in carriers (p=0.001, and p<0.001, respectively). This may imply that heterozygosity may be related with a silent obstructive pulmonary profile.

2009 Dequeker E, Stuhrmann M, Morris MA, Casals T, Castellani C, Claustres M, et al. Best practice guidelines for molecular genetic diagnosis of cystic fibrosis and CFTR-related disorders – updated European recommendations. Eur J Hun Genet 2009; 17:51-65.

An increasing number of laboratories offering molecular genetic analysis of the CFTR gene and the growing use of commercial kits strengthen the need for an update of previous best practice guidelines (published in 2000). The importance of organizing regional or national laboratory networks, to provide both primary and comprehensive CFTR mutation screening, is stressed. Current guidelines focus on strategies for dealing with increasingly complex situations of CFTR testing. Diagnostic flow charts now include testing in CFTR-related disorders and in fetal bowel anomalies. Emphasis is also placed on the need to consider ethnic or geographic origins of patients and individuals, on basic principles of risk calculation and on the importance of providing accurate laboratory reports. Finally, classification of CFTR mutations is reviewed, with regard to their relevance to pathogenicity and to genetic counselling.

2009 Bartlett JR, Friedman KJ, Ling SC, et al. Gene Modifier Study Group. Genetic modifiers of liver disease in cystic fibrosis. JAMA 2009; 302:1076-1083. [PubMed]
A subset (approximately 3%-5%) of patients with CF develops severe liver disease with portal hypertension. The objective of the study was to assess whether any of 9 polymorphisms in 5 candidate genes (alpha(1)-antitrypsin or alpha(1)-antiprotease [SERPINA1], angiotensin-converting enzyme [ACE], glutathione S-transferase [GSTP1], mannose-binding lectin 2 [MBL2], and transforming growth factor beta1 [TGFB1]) are associated with severe liver disease in patients with CF. The authors concluded that the SERPINA1 Z allele is a risk factor for liver disease in CF. Patients who carry the Z allele are at greater risk (OR, approximately 5) of developing severe liver disease with portal hypertension.

2009 Thauvin-Robinet C. Munck A. Huet F. Génin E. Bellis G. Gautier E. et al. Collaborating Working Group on R117H.The very low penetrance of cystic fibrosis for the R117H mutation: a reappraisal for genetic counselling and newborn screening. J Med Genet 2009; 46:752-758. [PubMed]
Phenotypic variability associated with certain mutations makes genetic counselling difficult, notably for R117H, whose disease phenotype varies from asymptomatic to classical CF. The high frequency of R117H observed in CF newborn screening has also introduced diagnostic dilemmas. The aim of this study was to evaluate the disease penetrance for R117H in order to improve clinical practice. The phenotypes in all individuals identified in France as compound heterozygous for R117H and F508del, the most frequent CF mutation, were described. The allelic prevalences of R117H (p(R117H)), on either intron 8 T5 or T7 background, and F508del (p(F508del)) were determined in the French population, to permit an evaluation of the penetrance of CF for the [R117H]+[F508del] genotype. Clinical details were documented for 184 [R117H]+[F508del] individuals, including 72 newborns. The disease phenotype was predominantly mild; one child had classical CF, and three adults' severe pulmonary symptoms. In 5245 healthy adults, p(F508del) was 1.06%, p(R117H;T7) 0.27% and p(R117H;T5)<0.01%. The theoretical number of [R117H;T7]+[F508del] individuals in the French population was estimated at 3650, whereas only 112 were known with CF related symptoms (3.1%). The penetrance of classical CF for [R117H;T7]+[F508del] was estimated at 0.03% and that of severe CF in adulthood at 0.06%. The authors suggest that these results suggest that R117H should be withdrawn from CF mutation panels used for screening programmes. The real impact of so-called disease mutations should be assessed before including them in newborn or preconceptional carrier screening programmes.

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